Sanguinarine inhibits the tumorigenesis of gastric cancer by regulating the TOX/DNA-PKcs/ KU70/80 pathway

Abstract

Sanguinarine (SAG), a benzophenanthridine alkaloid extracted from Sanguinaria canadensis, exerts antioxidant, anti-inflammatory and antiproliferative activities in a variety of malignancies. However, the underlying mechanisms by which SAG affects the tumorigenesis of gastric cancer (GC) are unclear. The common targets of SAG and GC were identified by network pharmacology, and the association of thymocyte selection-associated high mobility group box (TOX) with the clinicopathological characteristics and prognosis of patients with GC was analyzed by using datasets from The Cancer Genome Atlas (TCGA). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays, colony formation assays, flow cytometry analysis, and a xenograft tumor model were conducted to assess the effects of SAG on the growth of GC cells, and Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were used to determine the effects of SAG on the TOX/DNA-PKcs/KU70/80 signaling pathway. We identified 9 collective targets of SAG and GC, of which TOX expression levels were dramatically downregulated in GC tissues compared with adjacent normal tissues, and a low expression of TOX served as an independent prognostic factor of poor survival in patients with GC. SAG suppressed cell viability, colony formation and in vivo tumorigenesis and induced cell apoptosis and cell cycle arrest. Furthermore, SAG increased the expression levels of TOX but decreased those of DNA-PKcs and KU70/80 in GC cells. Our findings indicate that SAG inhibits the tumorigenesis of GC cells by regulating TOX/DNA-PKcs/KU70/80 signaling and may provide therapeutic strategies for the treatment of GC.